rs2305035

Variant names:

• chr3-105720182-G-A
• rs2305035
• NM_170662.5:c.1272C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-105720182-G-A
• chr3-105720182-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_170662.5(CBLB):​c.1272C>T​(p.Asp424Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,612,752 control chromosomes in the GnomAD database, including 39,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.21 (3630 hom., cov: 31)
  • Exomes 𝑓: 0.22 (36168 hom.)
• Consequence: CBLB NM_170662.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.160
• Publications: 29 publications found

Genes affected

CBLB (HGNC:1542): (Cbl proto-oncogene B) This gene encodes an E3 ubiquitin-protein ligase which promotes proteosome-mediated protein degradation by transferring ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate. The encoded protein is involved in the regulation of immune response by limiting T-cell receptor, B-cell receptor, and high affinity immunoglobulin epsilon receptor activation. Studies in mouse suggest that this gene is involved in antifungal host defense and that its inhibition leads to increased fungal killing. Manipulation of this gene may be beneficial in implementing immunotherapies for a variety of conditions, including cancer, autoimmune diseases, allergies, and infections. [provided by RefSeq, Sep 2017]

CBLB Gene-Disease associations (from GenCC):

• autoimmune disease, multisystem, infantile-onset, 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-105720182-G-A is Benign according to our data. Variant chr3-105720182-G-A is described in ClinVar as Benign. ClinVar VariationId is 3055764.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBLB	NM_170662.5	c.1272C>T	p.Asp424Asp	synonymous_variant	Exon 10 of 19	ENST00000394030.8	NP_733762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBLB	ENST00000394030.8	c.1272C>T	p.Asp424Asp	synonymous_variant	Exon 10 of 19	1	NM_170662.5	ENSP00000377598.4

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32599 AN: 151802 Hom.: 3625 Cov.: 31

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.225 AC: 56304 AN: 250508 AF XY: 0.218

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.323

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.219 AC: 320188 AN: 1460832 Hom.: 36168 Cov.: 34 AF XY: 0.217 AC XY: 157441 AN XY: 726750

African (AFR) AF: 0.195 AC: 6531 AN: 33466

American (AMR) AF: 0.316 AC: 14086 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3671 AN: 26128

East Asian (EAS) AF: 0.230 AC: 9122 AN: 39686

South Asian (SAS) AF: 0.145 AC: 12501 AN: 86212

European-Finnish (FIN) AF: 0.274 AC: 14604 AN: 53360

Middle Eastern (MID) AF: 0.147 AC: 844 AN: 5746

European-Non Finnish (NFE) AF: 0.221 AC: 245826 AN: 1111228

Other (OTH) AF: 0.215 AC: 13003 AN: 60368

GnomAD4 genome AF: 0.215 AC: 32623 AN: 151920 Hom.: 3630 Cov.: 31 AF XY: 0.217 AC XY: 16136 AN XY: 74208

African (AFR) AF: 0.189 AC: 7814 AN: 41442

American (AMR) AF: 0.257 AC: 3922 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 495 AN: 3472

East Asian (EAS) AF: 0.234 AC: 1205 AN: 5154

South Asian (SAS) AF: 0.148 AC: 713 AN: 4808

European-Finnish (FIN) AF: 0.271 AC: 2857 AN: 10530

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14953 AN: 67954

Other (OTH) AF: 0.190 AC: 401 AN: 2110

Alfa AF: 0.214 Hom.: 6850

Bravo AF: 0.215

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.215

EpiControl AF: 0.205

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CBLB-related disorder Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.5
DANN	Benign	0.55
PhyloP100		0.16
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2305035; hg19: chr3-105439026; COSMIC: COSV51421248;